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WO2007059871A1 - Hydroxy-substituted diphenylazetidinones for the treatment of hyperlipidaemia - Google Patents

Hydroxy-substituted diphenylazetidinones for the treatment of hyperlipidaemia

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Publication number
WO2007059871A1
WO2007059871A1 PCT/EP2006/010840 EP2006010840W WO2007059871A1 WO 2007059871 A1 WO2007059871 A1 WO 2007059871A1 EP 2006010840 W EP2006010840 W EP 2006010840W WO 2007059871 A1 WO2007059871 A1 WO 2007059871A1
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WO
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Patent type
Prior art keywords
phenyl
alkyl
compound
mg
fluoro
Prior art date
Application number
PCT/EP2006/010840
Other languages
German (de)
French (fr)
Inventor
Gerhard Jaehne
Wendelin Frick
Andreas Lindenschmidt
Hubert Heuer
Hans-Ludwig Schaefer
Werner Kramer
Wolfgang Schmider
Original Assignee
Sanofi-Aventis Deutschland Gmbh
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08Bridged systems

Abstract

The invention relates to compounds of the formula (I) in which R1, R2, R3, R4, R5 and R6 are defined as specified, and to their physiologically compatible salts. The compounds are suitable, for example, as hypolipidaemic drugs.

Description

description

HYDROXY-SUBSTITUTED DIPHENYLAZETTDINONE for treating hyperlipidemia

The invention relates to hydroxy-substituted Diphenylazetidinones and their physiologically acceptable salts.

There have been already low resorbierebare Diphenylazetidinones and their use for treating hyperlipidemia (PCT / EP03 / 05816, PCT / EP03 / 05815 and PCT / EP03 / 05816).

The invention had the object of providing further compounds available which display a therapeutically utilizable hypolipidemic action. In particular, the task was to find new compounds which have from those described in the prior art compounds, lower liver mirror. The lower levels liver reduce the burden on the liver and reduce the possibility of drug-drug interactions.

The object is achieved by compounds that carry an additional hydroxyl in 2 'position.

The invention therefore relates to compounds of the formula I,

wherein mean

R1, R2, R3, R4, R5, R6 are independently (Ci-C 3 o) -alkylene- (LAG) n, where n = 1 - 5 can be and where one or more carbon atoms of the alkylene radical (by -S O) n -, with n = 0 - 2, -O-, - (C = O) -, - (C = S) -, -CH = CH-,

_C = C-, -N ((Ci-C 6) -alkyl) -, -N (phenyl) -, -N ((C 1 -C 6) -alkyl-phenyl) -, -N (CO- (CH 2) i.io-COOH) -, -N (CO- (Ci-C8) alkyl) -, (-N CO- (C 3 -C 8) cycloalkyl), N (CO- (CH 2) 0 -io-aryl), -N (CO- (CH2) io-0- heteroaryl), -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C 3 - Ci 0) cycloalkyl or

Heterocycloalkyl may be substituted;

H, F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (C r C6) alkyl, CONH2, CONH (Ci-C 6) alkyl, CON [(Ci-C 6) alkyl] 2, (C r C6) alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, O- (Ci-C 6) -alkyl, where in the alkyl radicals one, several, or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SOzNH -CeJ ^ alkyl, Nf SO 2 (C 1 - C 6) alkyl] 2, S- ( C 1 -C 6) -alkyl, S- (CH 2) n -phenyl, SO- (C 1 -C 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - (C 6) -alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times by F, Cl, Br, OH, CF 3, NO 2,

CN, OCF 3, O- (Ci-C 6) -alkyl, (dC 6) -alkyl, NH 2 may be substituted; NH 2, NH ^ d-CeJ-alkyl, N ((Ci-C 6) -alkyl) 2, NH (C 1 -Cy) -acyl, phenyl, O- (CH 2) n -phenyl, where n = O - may be 6, wherein the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (d-CβJ alkyl, (C 1 -ce) -AIk ^, NH 2, NH (C r C6) alkyl, N ((C 1 -C 6) -alkyl) 2, SO 2 -

CH 3, COOH, COO- (CrC 6) alkyl, CONH 2;

R7 F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COOtd-QOAlkyl, CONH 2,

CONHtd-CeJAlkyl, CON [(C 1 -C 6) alkyl] 2, (CrC 6) alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SOzNHfd-CeJ-alkyl, SO 2 N f (C 1 - C 6) alkyl] 2, S- (Ci -C 6) -alkyl, S- (CH 2) n -phenyl, SO- (C r C6) -alkyl, SO- (CH 2) n -phenyl, SOHD Ceϊ-alkyl, SO 2 - (CH 2 ) n -phenyl, where n = 0 - 6 and the phenyl radical can be up to two times (with F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O- Ci-C 6) alkyl, (C r C6) alkyl, NH 2 may be substituted; NH 2, NH- (C r C6) alkyl, NKD-CeJ-alkyl); ,, NH (C 1 -Cr) -acyl, aryl, O- (CH 2) n -

Aryl, where n = O - 6 may be, wherein the aryl ring can be a to 3-fold substituted by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 - C 6) - alkyl, (C r C6) alkyl, NH 2, NH (C 1 -C 6) -alkyl, N ((C 1 -C 6) -alkyl) 2, SO 2 -CH 3, COOH , COO-tCrCeJ -alkyl, CONH 2;

LAG C 4 -C 10 -cycloaliphatischer substituted with 2 to 9 hydroxy

Radical or C 2 -C 10 -aliphatic substituted with 2 to 10 hydroxy radical, wherein one or more hydroxy groups may be replaced by a -NHR8 group; Amino acid residue, oligopeptide residue comprising 2 to 9 amino acids; acyclic, mono- or bicyclic trialkylammonium radical, acyclic, mono or bicyclic trialkylammoniumalkyl radical, where up to three carbon atoms may be replaced by N, O or S (O), with n = 0-2; N-alkylated heteroaromatics such. B. imidazolium or pyridinium;

-O- (SO 2) -OH; - (CH 2) O-10 -SO 3 H; - (CH 2) 0 - 10 -P (O) (OH) 2, - (CH 2) 0-10 -O- P (O) (OH) 2, - (CH 2) 0-10 -C (= NH) (NH 2); - (CH 2) 0-10 -C (= NH) (NHOH); -NR8- C (= NR9) (NR10R11); wherein n = 1 - 5 and R8, R9, R10 and R11 independently of one another H, (Ci-CβJ alkyl, phenyl, (CRCE) alkyl-phenyl, (C 3 -C 8) cycloalkyl), -C ( O) - (C 1 -C 6) alkyl, -C (O) - (C 3 -C 8) cycloalkyl may be;

where always at least one of the radicals R1 to R6 has the meaning (C 1 -C 30) -alkylene- (LAG) n, where n = 1-5 can be and wherein one or more C atoms of the alkylene group represented by -S (O) n -, with n = O - 2, -O-, - (C = O) -, - (C = S) -, -CH = CH-, - C≡C-, -N ((C 1 -C 6) -alkyl) -, -N (phenyl) -, -N ((C 1 -C 6) -alkyl-phenyl) -, -N (CO- (CH 2) 1-10 - COOH) -, -N (CO- (C r C 8) alkyl) -, -N (CO- (C 3 -C 8) cycloalkyl), N (CO- (CH 2) 0-10 -aryl), - N (CO- (CH 2) o-io-heteroaryl), -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times by R7 substituted (C 3 -C 0) - cycloalkyl or heterocycloalkyl radicals may be replaced; must have,

as well as their pharmaceutically acceptable salts.

Compounds of formula I are those wherein at least one of the radicals R1 to R6 has the meaning (Ci-C 2 o) -alkylene- (LAG), where one or more carbon atoms of the alkylene group by -O-, - (C = O ) -, -N ((Ci-C 6) -alkyl) -, -N (CO- (CH 2) I - I o-COOH) - or - NH-, or by up to trisubstituted aryl or heteroaryl radicals with R7 or (C 0 -C 3) cycloalkyl or heterocycloalkyl radicals may be replaced by up to four times substituted with R7, possesses.

Particularly preferred are compounds of the formula I 1 wherein one of the radicals R1 or R3 has the meaning (Ci-C 12) alkylene- (LAG), where one or more carbon atoms of the alkylene group by -O-, - (C = O ) -, -N (CH 3) -, or -NH-, or be replaced by up three times with R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C 3 -C 10) cycloalkyl or heterocycloalkyl radicals may ,

Very particularly preferred compounds of formula I wherein one of R1 or R3 is (Ci-C 5) -alkylene- (LAG); wherein one or more C atoms of the alkylene group by -O-, - (C = O) - or -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C 3 -C 10) cycloalkyl or heterocycloalkyl groups may be replaced.

Still further preferred compounds of the formula I wherein one of R1 or R3 is -O-CH 2 -aryl-CH 2 - (LAG), -CH 2 -O- (C = O) heterocycloalkyl (LAG) , - CH 2 -NH- (C = O) heterocycloalkyl (C = O) -CH 2 - (LAG), -CH2 heterocycloalkyl (LAG), -NH- (C = O) heterocycloalkyl ( LAG) or -O- (C = O) heterocycloalkyl (LAG) has.

Further preferred are compounds of formula I wherein one of the radicals R1 or R3 the meaning of -CH 2 -O- (C = O) -Heterocycloaikyl- (LAG), -CH 2 -NH- (C = O) - heterocycloalkyl ( C = O) -CH 2 - (LAG), -CH2 heterocycloalkyl (LAG), -NH- (C = O) - heterocycloalkyl (LAG) or -O- (C = O) heterocycloalkyl (LAG ) has.

Further preferred are compounds of formula I, wherein one of the radicals R1 or R3

- NN - heterocycloalkyl as 1, 4-Piperazindiylrest (^^) has.

Further preferred are compounds of formula I, wherein the group LAG is a sulfate radical (-0-SO 3 H), a sulfonic acid (-SO 3 H), a mono- or bicyclic cycloalkyl in which one or more carbons are replaced by nitrogen, or is a mono or bicyclic trialkylammoniumalkyl residue.

A mono- or bicyclic trialkylammonium radical, a mono- or bicyclic cycloalkyl in which one or more carbons are replaced with nitrogen and the nitrogen carries an additional hydrogen and positive charge understood.

For example, groups such as

Wherein n, m and p are independently 0 - 10 may be, and one or more CH2 groups independently of one another by O, S (O) n, where n = 0 - may be 2, NH, N- (Ci-Ci O) -alkyl, N-phenyl or N-CH 2 -phenyl may be replaced.

A mono- or bicyclic trialkylammoniumalkyl residue is a mono- or bicyclic cycloalkyl in which one or more carbons are replaced with nitrogen and the nitrogen carries a positive charge and additional alkyl understood. For example, groups such as

or

or

or

understood, where n, m and p are independently 0 - 10 can be, and one or more CH2 groups independently of one another by O, S (O) n, where n = 0 - may be 2, NH, N- (C 1 -C O) -alkyl, N-phenyl or N-CH 2 -phenyl, and may be replaced

Alkieinen straight or branched alkyl radical having 1 to 20 carbon atoms.

From N-alkylated heteroaromatic residues such as Alk '(CH 2) n ~

N.

Alk 1 - 'N ^ N' - (CH,) n> Alk;

N ^ N + - (CH,) n. Alk; / 1 V + - (CH 2) n -NN

NN: V - = /

understood, where n is 0 - 10 may be and Alki means a straight or branched alkyl radical having 1 to 20 carbon atoms.

Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the initial or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid and organic acids such as acetic acid,

Benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, and tartaric acid. For medical purposes, particularly preferably the chlorine salt is used. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), zinc salts of trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol) -, diethanolamine, lysine -, arginine, choline, meglumine or ethylenediamine salts.

Salts with a pharmaceutically acceptable anion or cation are also included in the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and / or for use in nontherapeutic, for example in-vitro applications.

Another aspect of this invention are prodrugs of the compounds of the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.

The compounds of the invention may also exist in different polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.

Below, all references to "compound (s) of formula (I)" refer to compound (s) of formula (I) as described above, and their salts, solvates and physiologically functional derivatives as described herein. The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal pharmaceuticals for the treatment of lipid metabolism disorders, especially hyperlipidemia. The compounds of the formula I are likewise suitable for influencing the serum cholesterol level and for preventing and treating arteriosclerotic symptoms.

The compound (s) of formula (I) may also be administered in combination with other active ingredients.

The amount of a compound according to formula (I) which is required to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient , In general, the daily dose is in the range of 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram bodyweight, for example 0.1-10 mg / kg / day. Tablets or capsules, may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the salt derived from the diphenylazetidinone ion. For the prophylaxis or therapy of the abovementioned conditions, the compounds according to formula (I) can be used themselves as the compound, but they are preferably with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and is not harmful for the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as single dose, for example as tablet, which may contain wt .-% of the active ingredient of 0.05% to 95 wt. Further pharmaceutically active substances may likewise be present, including further compounds according to formula (I). The pharmaceutical compositions of the invention can be prepared, which consist essentially in mixing the ingredients with pharmacologically acceptable carriers and / or excipients are mixed by one of the known pharmaceutical methods.

Inventive pharmaceutical compositions are those that administration are suitable (for example sublingual) for oral and peroral, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition being treated and on the nature of the compound used according to formula (I) , Coated formulations and coated slow-release in the context of the invention. acid- and gastric juice-resistant formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate,

Hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets,

Lozenges or tablets, each containing a predetermined amount of the compound according to formula (I); as powders or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. by any suitable pharmaceutical method These compositions may, as already mentioned, be prepared that has a

Step comprises, at which the active ingredient and the carrier (which may consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary. Thus a tablet, for example, can be prepared by pressing a powder or granules of the compound, or is formed, optionally with one or more accessory ingredients. Compressed tablets may be prepared by tableting the compound in free-flowing form such as a powder or granules, optionally mixed are surface-active / dispersing agents in a suitable machine with a binder, lubricant, inert diluent and / or one (or more). Molded tablets may be made by molding the pulverulent compound, moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula (I) with a flavoring, normally arabic or sucrose and gum tragacanth, and pastilles comprising the compound in an inert base such as gelatin include and glycerin or sucrose and acacia.

Further active ingredients for combination products are:

All antidiabetics which are mentioned in the Red List 2005, Chapter 12; all weight-reducing agents / appetite suppressants which are gennant in the Red List 2005, chapter 1; all lipid-lowering agents which are mentioned in the Red List 2005, Chapter 58th They can be combined with the inventive compound of formula I in particular for a synergistic improvement. The administration of the

Active ingredient combination can take place either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active compounds are present in one pharmaceutical preparation. Most of the active ingredients listed below are in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville, 2001 discloses.

Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 or those as described in WO2005005477 (Novo Nordisk) insulins, fast-acting (see US 6,221, 633), inhalable insulins such as, z. B. Exubera ® or oral insulins such as. B. IN-105 (Nobex) or Oral-lyn ™ (Generex Biotechnology), GLP-1 derivatives, such as exenatide,

Liraglutide or those disclosed in WO 98/08871, WO2005027978 of Novo Nordisk A / S, in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuticals), and orally effective hypoglycemic agents.

The orally effective hypoglycemic active ingredients include preferably sulfonylureas,

biguanides,

meglitinides,

Oxadiazolidinediones, thiazolidinediones,

Glucosidase inhibitors,

Inhibitors of glycogen phosphorylase,

Glucagon antagonists,

Glucokinase activators, inhibitors of fructose-1, 6-bisphosphatase

Modulators of glucose transporter 4 (GLUT4),

Inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),

GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and

WO 99/03861 disclosed by Novo Nordisk A / S, inhibitors of dipeptidylpeptidase IV (DPP-IV),

Insulin sensitizers,

Inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or

Glycogenolysis,

Modulators of glucose uptake, of glucose transport and of glucose,

Inhibitors of 11 beta-HSD1,

Inhibitors of protein tyrosine phosphatase 1 B (PTP1B),

Modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients,

Compounds which reduce food intake,

Compounds that increase thermogenesis,

PPAR and RXR modulators and

Agents acting on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of formula I is in

administered combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, L-659,699th

In one embodiment of the invention, the compound of formula I in combination with a cholesterol such as ezetimibe, tiqueside, pamaqueside, FM-VP4 (sitostanol / campesterol ascorbyl phosphate; Forbes Medi-Tech, WO2005042692), MD-0727 (Microbia Inc. , WO2005021497) or with compounds as described in WO2002066464 (Kotobuki Pharmaceutical Co. Ltd.), or WO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZeneca AB) describes administered.

In one embodiment of the invention, the compound of formula I in combination with a PPAR gamma agonist such as, for example, rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483, CS-011 (Rivoglitazon) is administered.

In one embodiment of the invention, the compound of formula I in combination with PPAR alpha agonist, such as for example, GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-administered 10,945th

In one embodiment of the invention, the compound of formula I in combination with a mixed PPAR alpha / gamma agonist, such as muraglitazar, tesaglitazar, Naveglitazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847 described, or as described in PCT / US 00/11833, PCT / US 00/11490, DE10142734.4 or in JPBerger et al., TRENDS in Pharmacological Sciences 28 (5), 244-251, 2005 administered.

In one embodiment of the invention, the compound of formula I in combination with a PPAR delta agonist such as GW-501516 is administered. In one embodiment, the compound of formula I in combination with metaglidasen or with MBX-2044 or other partial PPAR gamma agonists / antagonists will be administered in one embodiment of the invention, the compound of formula I in combination with a fibrate, such as fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compound of formula I in combination with an MTP inhibitor such as implitapide, BMS-201038, R-103757 or those described in WO2005085226 describes administered.

In one embodiment of the invention, the compound of formula I in combination with a CETP inhibitor such as, for example, torcetrapib or JTT-705 administered.

In one embodiment of the invention, the compound of formula I in combination with bile acid absorption inhibitor (see, for example US 6,245,744, US 6,221, 897 or WO00 / 61568), as described, for example, HMR 1741 or those described in DE 10 2005 033099.1 and DE 10 2005 033100.9, administered.

In one embodiment of the invention, the compound of formula I in combination with a polymeric bile, such as cholestyramine, colesevelam administered.

In one embodiment of the invention, the compound of formula I in combination with an LDL receptor inducer (see US 6,342,512), such as HMR1171, HMR1586 or those as described in WO2005097738, is administered.

In one embodiment, the compound of formula I in combination with Omacor® (omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid) is administered.

In one embodiment of the invention, the compound of formula I in combination with an ACAT inhibitor, such as avasimibe.

In one embodiment of the invention, the compound of formula I in combination with an antioxidant such as OPC-14117, probucol, tocopherol, ascorbic acid, .beta.-carotene or selenium is administered.

In one embodiment of the invention, the compound of formula I in combination with a vitamin, such. Example, vitamin B6 or vitamin B12 administered.

In one embodiment of the invention, the compound of formula I in combination with a lipoprotein lipase modulator such as, for example, administered Ibrolipim (NO-1886).

In one embodiment of the invention, the compound of formula I in combination with an ATP citrate lyase inhibitor such as, for example, administered SB-204990.

In one embodiment of the invention, the compound of formula I in combination with a squalene synthetase inhibitor, such as BMS-188494 or as described in WO2005077907, is administered.

In one embodiment of the invention, the compound of formula I in combination with a lipoprotein (a) antagonist, such as gemcabene (CI-1027) administered.

In one embodiment of the invention, the compound of formula I in combination with an HM74A receptor agonist such as, for example, nicotinic acid administered.

In one embodiment of the invention, the compound of formula I in combination with a lipase inhibitor, (ATL-962) is administered as for example, orlistat or cetilistat.

In one embodiment of the invention, the compound of the formula I is administered in combination with insulin. In one embodiment, the compound of formula I in combination with a sulphonylurea, such as tolbutamide, glibenclamide, glipizide or glimepiride is administered.

In one embodiment, the compound of formula I in combination with a biguanide, as for example metformin administered.

In yet another embodiment, the compound of formula I in combination with a meglitinide, such as repaglinide or nateglinide, is administered.

In one embodiment, the compound of formula I in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 of Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - phenyl] methyl - [(3,4-dihydro-3-methyl-4-oxo-2-chinazolinylmethoxy]] -2,4-thiazolidinedione administered.

In one embodiment, the compound of formula I in combination with an α-glucosidase inhibitor, such as miglitol or acarbose is administered.

In one embodiment, the compound of formula I is administered in combination with an agent acting on the ATP-dependent potassium channel of the beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of formula I in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone will , insulin and lovastatin, etc..

In one embodiment, the compound of formula I in combination with an inhibitor of glycogen phosphorylase, is such as PSN-357 or FR-258900, administered or those described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932 described. In one embodiment, the compound of formula I in combination with glucagon receptor antagonists, is described, such as A-770077 or NNC-25-2504 or as described in WO2004100875, WO2005065680, administered.

In one embodiment, the compound of formula I in combination with activators of glucokinase, such. B. LY-2121260 (WO2004063179), PSN-105, PSN-110, GKA-50 or those as such. As are described in WO2004072031, or WO2004072066 or WO2005080360 administered.

In one embodiment, the compound of formula I in combination with an inhibitor of gluconeogenesis, such. B. FR-225654, administered.

In one embodiment, the compound of formula I in combination with inhibitors of fructose-1, 6-bisphosphatase (FBPase) is administered, such as CS-917.

In one embodiment, the compound of formula I in combination with modulators of glucose transporter 4 (GLUT4), such as. B. KST-48 (D.-O. Lee et al .: Arzneim.-Forsch. Drug Res. 54 (12), 835 (2004)) administered.

In one embodiment, the compound of formula I in combination with

Inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), as z. As are described in WO2004101528 administered.

In one embodiment, the compound of formula I in combination with inhibitors of dipeptidylpeptidase IV (DPP-IV) is such. B. vildagliptin (LAF-237)

Sitagliptin (MK-0431), saxagliptin ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X or as described in WO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312, WO2005 / 012308, PCT / EP2005 / 007821, PCT / EP2005 / 008005, PCT / EP2005 / 008002, PCT / EP2005 / 008004, PCT / EP2005 / 008283, DE 10 2005 012874.2 and DE 10 2005 012873.4 describes administered. in one embodiment, the compound of formula I in combination with inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD1), such as, for example, BVT-2733 or those as z. B. in WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877, WO2005097759 described administered.

In one embodiment, the compound of formula I in combination with inhibitors of protein tyrosine phosphatase 1 B (PTP1 B), as z. B. in WO200119830-31, WO200117516, WO2004506446, WO2005012295, PCT / EP2005 / 005311, PCT / EP2005 / 005321, PCT / EP2005 / 007151, PCT / EP2005 / or DE 10 2004 060542.4 described administered.

In one embodiment, the compound of formula I in combination with modulators of the sodium-dependent glucose transporter 1 or 2 (SGLT1, SGLT2), as for example, KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or as described, for , As in WO2004007517, WO200452903, WO200452902, PCT / EP2005 / 005959,

WO2005085237, JP2004359630 or by AL Handion in Expert Opin. Ther. Patents (2005) 15 (11), 1531-1540 described administered.

In one embodiment, the compound of formula I is administered in combination with modulators of GPR40.

In one embodiment, the compound of formula I in combination with inhibitors of hormone-sensitive lipase (HSL), such as. As described in WO2005073199.

In one embodiment, the compound of formula I in combination with inhibitors of acetyl-CoA carboxylase (ACC) such as is. Example, those as described in W0199946262, WO200372197, WO2003072197, WO2005044814 describes administered.

In one embodiment, the compound of formula I in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), as for example those as described in WO2004074288, is administered.

In one embodiment, the compound of formula I in combination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), as z. B. in US2005222220, WO2005085230, PCT / EP2005 / 005346, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117 described.

In one embodiment, the compound of formula I in combination with an inhibitor of protein kinase C beta (PKC beta), as z. B. ruboxistaurin administered.

In one embodiment, the compound of formula I in combination with an endothelin-A receptor antagonist, such. B. avosentan (SPP-301) administered.

In one embodiment, the compound of formula I in combination with inhibitors of "l-kappaB kinase" (IKK inhibitors), as administered z. B. WO2001000610, are described in WO2001030774, WO2004022553, WO2005097129.

In one embodiment, the compound of formula I in combination with modulators of the glucocorticoid receptor as such. As described in WO 2005/090336 administered.

In another embodiment, the compound of Formula I in combination with CART modulators (see is "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A. et al .: Hormone and Metabolic Research (2001 ), 33 (9), 554-558); NPY antagonists such as naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2- ylamino) methyl] -cyclohexylmethyl} -amide hydrochloride (CGP 71683A); Peptide YY 3-36 (PYY3-36) or analogous compounds, such as. For example, CJC-1682 (PYY3-36 conjugated with human serum albumin via Cys34), CJC-or 1643 (derivative of PYY3-36 which conjugates to serum albumin in vivo) or those as are described in WO2005080424;

Cannabinoid receptor 1 antagonists (such as rimonabant, SR147778 or those as are described in z. B. EP 0656354, WO 00/15609, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776 WO2003040107,

WO2003007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456,

WO2005063761-62, WO2005061509, WO2005077897 are described); MC4 agonists (for example, 1-amino-1, 2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a- benzyl-2-methyl-3-oxo-2,3,3a, 4,6, 7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro- phenyl) -2-oxo-ethyl] -amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those as are described in WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201 WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797, US20040224901,

WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, EP1538159, WO2004072076, WO2004072077 are described; Orexin receptor antagonists (for example 1- (2-methyl-benzoxazol-6-yl) -3- [1, 5] naphthyridin-4-yl-urea hydrochloride (SB-334867-A) or those as z. B . in WO200196302, WO200185693, WO2004085403, are described in WO2005075458); Histamine H3 receptor agonists (eg. B. 3-cyclohexyl-1- (4,4-dimethyl-1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propan-1 -one oxalic acid salt (WO 00/63208) or those as are described in WO200064884, WO2005082893); CRF antagonists (for example [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585) ); CRF BP antagonists (for example urocortin); Urocortin agonists; ß3-agonists (such as 1- (4-Chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl-1 H-indol-6-yloxy) ethylamino] ethanol hydrochloride (WO 01 / 83451)); MSH (melanocyte-stimulating hormone) agonists; MCH (melanin-concentrating hormone) receptor antagonists (such as, for example, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or those compounds are as described in WO2003 / 15769, WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2003033476, WO2002006245, WO2002002744, WO2003004027, FR2868780); CCK-A agonists (such as {2- [4- (4-chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl- indol-1-yl} acetic acid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150) or SSR-125180); Serotonin reuptake inhibitors (for example dexfenfluramine); mixed serotonin and noradrenergic compounds (for example WO 00/71549);

5-HT receptor agonists, for example 1- (3-ethyl-benzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111);

5-HT2C receptor agonists (such as APD 356 or BVT-933 or those described in WO200077010, WO20077001-02, WO2005019180, WO2003064423, WO200242304, WO2005082859 are described);

5-HT6 receptor antagonists as are described for example in WO2005058858; Bombesin receptor agonists (BRS-3 agonists; galanin receptor antagonists;

Growth hormone (for example human growth hormone or AOD-9604);

Growth hormone-releasing compounds (6-benzyloxy-1- (2-diisopropylamino ethylcarbamoyO-S ^ -dihydro-I H-isoquinolin ^ -carbonsäuretertiärbutylester (WO 01/85695));

Growth hormone secretagogue receptor antagonists (ghrelin antagonists) such as.

B. A-778193 or those as are described in WO2005030734;

TRH agonists (see, for example EP 0462884); uncoupling protein 2 or 3 modulators; Leptin agonists (see, eg, Lee, Daniel W .; Leinung, Matthew C; Rozhavskaya-

Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (9), 873-881);

DA agonists (bromocriptine, doprexin);

Lipase / amylase inhibitors (for example WO 00/40569); Inhibitors of diacylglycerol O-acyltransferases (DGATs) such. B.

US2004 / 0224997, WO2004094618, WO200058491, WO2005044250,

WO2005072740, JP2005206492, WO2005013907 described;

Inhibitors of fatty acid synthase (FAS) such as, for example, C75 or those as in

WO2004005277 described; oxyntomodulin;

Oleoyl-estrone

or agonists of the thyroid hormone receptor (thyroid hormone receptor agonists) such. B: KB-2115 or those as described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, administered WO2005092316 described.

In one embodiment of the invention, the further active ingredient is leptin; See, eg, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; FRUHBECK, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622. In one embodiment, the further active ingredient is dexamphetamine or amphetamine.

In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

In yet another embodiment, the other active ingredient is sibutramine.

In one embodiment, the further active ingredient is mazindol or phentermine.

In one embodiment, the compound of formula I in combination with bulking agents, preferably insoluble bulking agents (see for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep-Oct). 18 (5), 230-6.) Caromax.RTM is a carob-containing product from. Nutrinova Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)) administered. Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®. Caromax.RTM ® can in this case in the form of food, such as administered in bakery products or muesli bars.

It is understood that any suitable combination of the compounds according to the invention with one or more of the aforementioned compounds is, and optionally one or more further pharmacologically active substances is included in the scope of the present invention falling viewed. CH 2 -CH 3

-501

LY-674 KRP-101

LY-510929 GW-501516

FR-225654

The invention further relates both stereoisomer mixtures of the formula I and the pure stereoisomers of the formula I, and diastereomer mixtures of the formula I and the pure diastereomers. The separation of mixtures by chromatographic means.

racemic and enantiomerically pure compounds of formula I having the following structure are preferred:

R4

As amino are preferably split off by catalytic hydrogenation of the benzyloxycarbonyl (Z-) group represented by weak acids cleavable 2- (3,5-Dimethyloxyphenyl) propyl (2) oxycarbonyl (Ddz) or trityl (Trt) radical which by 3M hydrochloric acid dissociable t-butyl carbamate (BOC -) - radical and the removed using secondary amines 9-fluorenylmethyloxycarbonyl (Fmoc) radical which.

The invention further relates to a process for the preparation of diphenylazetidinone of Formula I.

Y, W, Z, Y ', W, Z 1 can independently -NH-, -O-, - mean (C = O), phenyl, cycloalkyl, heterocycloalkyl, or a bond, and LAG may have the meanings as described earlier ,

The combination of - (CH 2) oiYWZ- (Co-C25) -alkylene-H in compound II may alternatively be on one of the other two phenyl rings.

The process for preparing the compounds of formula I is characterized in that protected, for example, an activated suitably

Carbamate or a protected in a suitable manner alpha, omega-diol, or a suitably protected alpha, omega-Halogenoalkohol or an alkylating agent with an amine or a hydroxy compound of the formula II, wherein the hydroxy in the 3 'or 2' position can be suitably protected, are reacted. After removal of any protecting group, the Compound E of the formula Il can be linked in a further step with the group LAG, for example with the formation of Schwefelsäuremonoamiden.

The following examples serve to further illustrate the invention without at the same described in Examples products and embodiments limit.

scheme 1

, 2,7-trimethyl-benzoin .31dioxin-4-one 2

200 g (1.31 mol) of 4-methyl-salicylic acid 1 l of acetone and 400 ml of acetic anhydride are dissolved in Fig.2. Under an argon atmosphere, 50 ml of conc at 0 ° C. Sulfuric acid was added dropwise. The reaction solution was stirred for a further 90 minutes at 0 0 C. Then approximately 1 I of acetone is distilled off and the residue treated with 1 I of n-heptane / ethyl acetate (4: 1) and 1 l of water was added. The aqueous phase is separated off and once more with 1 l of n-heptane / ethyl acetate (4: 1). The collected organic phase is washed 2 times with 500 ml of 10% sodium hydroxide solution, filtered over 250 ml of silica gel and concentrated. The oily residue is dissolved in a little n-heptane and inoculated with seed crystals. 137.5 g is obtained crystalline acetonide. 2

7-bromomethyl-2 1 2-dimethyl-benzori, 31dioxin-4-one 3

100 g (0:52 mole) of the acetonide 2 are dissolved in 1 l of carbon tetrachloride. After addition of 6 g of benzoyl peroxide for 2 hours refluxed. Thereafter, the mixture is cooled to room temperature and diluted with 500 ml of n-heptane / ethyl acetate (3: 1). This solution is filtered through silica gel and not completely evaporated to dryness (about 50 ml solvent residue). This solution is stored at -30 0 C overnight. The precipitated product is filtered off and obtained 69.5 g of crystalline benzyl bromide 3, which is still contaminated with a little peroxide.

Essiqsäure-2,2-dimethyl-4-oxo-4H-benzoin, 31dioxin-7-ylmethyl ester 4

55 g (0:20 mol) of benzyl 3 are dissolved in 550 ml DMF. After addition of 30 g (.0.37 mol) of sodium acetate is allowed to stand overnight. For workup, 700 ml of n-heptane / ethyl acetate (2: 1) was added and 500 ml of water. The aqueous phase is separated, the organic phase is washed 2 times with aqueous NaCl solution, filtered through silica gel and concentrated. The residue is purified by flash chromatography (n- heptane / ethyl acetate 4: 1: 1 to 2) and purified to obtain 22.9 g amorphous product. 4

2-Hydroxy-4-hvdroxymethyl-benzoic acid methyl ester 5

30 g (0:12 mol) of compound 4 suspended in 100 ml of methanol. With stirring, 300 ml of 1 M NaOMe / MeOH solution are added dropwise, whereby a short time a clear solution forms. After stirring for 30 minutes the solution with 320 ml of 1 M HCI / MeOH is acidified (while the solution is colorless) separated and dried over a little silica gel, the resultant NaCl. It is then concentrated and the residue dissolved in 100 ml of n-heptane / ethyl acetate (2: 1) were suspended. This solution is again filtered through silica gel and washed with n-heptane / ethyl acetate mixture. After fuming of the solvent gives 18.1 g of crude product. 5

2-benzyloxy-4-benzyloxymethyl-benzoic acid methyl ester β

18.1 g of crude product 5 are dissolved in 360 ml DMF and 36 ml of benzyl bromide. With ice bath cooling are added in portions a total of 15 g NaH (as a 55% suspension in paraffin oil) and then stirred for 1 hour at room temperature to stir. In order to destroy excess NaH and BnBr careful 4 ml of methanol are added dropwise. After 15 minutes, 1 I of n-heptane / ethyl acetate (3: 1) was added and extracted 3 times with water. The organic phase is filtered through silica gel, concentrated and the

Residue by flash chromatography (n-heptane / ethyl acetate 6: 1 to 2: 1). 21.4 g is obtained perbenzyliertes product 6. (2-benzyloxy-4-benzyloxymethyl-phenyl) -methanol 7

21.4 g (59.2 mmol) of methyl ester of 6 are dissolved in 270 ml of THF and cooled to 0 ° C. It is slowly added dropwise, followed by stirring for 15 minutes at 0 0 C A 1 M lithium aluminum hydride solution in diethyl ether at 0 ° C. Excess lithium aluminum hydride is destroyed by addition of 3 ml of ethyl acetate. To get a well filterable precipitate successively gently 4 ml of water, 4 ml of 10% sodium hydroxide solution and 8 ml of water are added. The precipitate is filtered through silica gel, washed with ethyl acetate and then concentrated. This gives 19.7 g of crude product. 7

2-benzyloxy-4-benzyloxymethyl-8 benzaldehvd

19.7 g of crude product 7 are dissolved in 300 ml of DMSO and 150 ml of acetic anhydride and 18 hours at room temperature, allowed to stand. This reaction solution is then diluted with 500 ml of n-heptane / ethyl acetate and washed 3 times with saturated NaCl solution, filtered through silica gel and concentrated. Residual acetic anhydride is fumed off with toluene and 19.2 g of aldehyde is obtained as a crude product 8. (2-benzyloxy-4-benzyloxymethyl-benzylidene) - (4-fluoro-phenyl) -amine 10

19.2 g of aldehyde 8 and 10 ml (103 mmol) of p-fluoroaniline 9 (Fluka) are boiled with 300 ml of toluene for 2 hours on a water and distilled while about 100 ml of toluene from. The remaining toluene is evaporated on a rotary evaporator and the residue is purified by flash chromatography (n-heptane / ethyl acetate 2: 1 + 1% triethylamine) and one obtains 25 g imine 10th

3-r2-r (2-benzyloxy-4-benzyloxymethyl-phenyl) - (4-fluoro-phenylamino) -methyll-5- (tert-butyl-dimethyl-silanyloxy) -5- (4-fluoro-phenyl) -pentanovn -4-phenyl-oxazolidin-2-one 12

5.0 g (10.6 mmol) oxazolidinone 11 are dissolved together with 2.1 ml of diisopropylethylamine in 50 ml methylene chloride and cooled under argon to 0 0 C. To this solution is slowly dropped into 8.8 ml of a 1 M TiCl / methylene chloride solution. Then, 5 minutes, warmed to 20 0 C and then cooled to -30 ° C. At -30 0 C a solution of 5.4 g (12.7 mmnol) imine is added dropwise in 15 ml of methylene chloride and stirred at 10 -30 0 C for 30 minutes. The reaction solution is extracted with 100 ml of water. The organic phase is filtered through 100 ml silica gel. The aqueous phase is again with 80 ml of n-heptane / ethyl acetate (2: 1), and the organic phase is used for the silica gel of the first filtration nachzuwaschen. The organic phase is concentrated and purified by flash chromatography (n-heptane / ethyl acetate 4: 1: 1 to 2). Obtained 4:34 g of product 12th

4- (2-benzyloxy-4-benzyloxymethyl-phenyl) -3-R3- (tert-butyl-dimethyl-silanyloxy) -3- (4- fluoro-phenyl) -propyll-1 - (4-fluoro-phenyl) - azetidin-2-one 13

4:34 g (4.8 mmol) of compound 12 are dissolved in 60 ml of toluene. Is added dropwise 3.4 ml of bis trimethylsilylacetamide (BSA) was added and cooled to 0 0 C. After addition of 1.7 ml of 1 M Tetrabuylammoniumfluorid (TBAF) in THF is allowed to warm to room temperature and stirred for 1 hour at room temperature. The reaction solution is filtered through silica gel and washed with ethyl acetate. purified and obtained 2.27 g of beta-Lactan 13 After distilling off the solvent, the residue with flash chromatography (: 1 to 2 1 n-heptane / ethyl acetate 4).

1- (4-Fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4- (2-hydroxy-4-hydroxymethyl-phenyl) azetidin-2-one 14

2.25 g (3:07 mmol) of lactam 13 are dissolved in 40 ml ethyl acetate and hydrogenated with 1 g of 10% Pd on charcoal for 3 hours at 6 bar hydrogen. The palladium activated carbon is removed on a little silica gel and the residue is purified by flash chromatography (n- heptane / ethyl acetate 4: 1: 1 to 2). This gives 640 mg of product 14 piperazin-1-carbonic acid 4- [3-R3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenvD- propyn-1- (4-fluoro-phenyl) -4-oxo-azetidin-2-yll-3-hydroxy-benzyl ester 15

O

690 mg (1.25 mmol) of compound 14 are dissolved in 10 ml acetonitrile. one after the other 0.5 ml is added triethylamine and 500 mg (1.9 mmol) of di-Su-CO (Fluka) is added and stirred for 30 minutes at room temperature. Then added dropwise, the reaction solution in a solution of 1 g of piperazine in 10 ml of acetonitrile and stirred for 1 hour. The heterogeneous reaction solution is directly by flash chromatography

(Methylene chloride / methanol / conc. Ammonia 100/7/1 30/5/1 then 30/10/3 then), and recrystallized to obtain 590 mg of product 15 as a colorless amorphous solid.

Piperazin-1-carbonic acid 4- (1- (4-fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-hvdroxy- propyn-4-oxo-azetidin-2-yl) -3- Hydroxy-benzyl ester 16

580 mg (0.87 mmol) of Compound 15 was dissolved in 10 ml THF. After addition of 5 ml 2 N aqueous HCl, allowed to stand at room temperature for 16 hours, the homogeneous solution. The solution is then by adding a mixture of methylene chloride / methanol / conc. Ammonia (10/30/30) basified and then concentrated. The residue is suspended in a little 30/5/1 and purified by flash chromatography (methylene chloride / methanol / conc. Ammonia 30/5/1 then 30/10/3) to give 400 mg of compound 16 is obtained as an amorphous solid of molecular weight 551.60 ( C 30 H 2 F 3I N 3 O 5); MS (ESI +): 552.24 (M + H +).

4- (4- (1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-oxo-azetidin-2-yl) - 3- hvdroxy- benzyloxycarbonyl) -piperazin-1-sulfamide ammonium salt 17 (example A)

560 mg (1.0 mmol) of compound 16 are dissolved in 15 ml of methanol and cooled to 0 0 C. After addition of 1 g Trimethylaminschwefeltrioxid complex mixture is stirred for 2 hours at 0 0 C. The reaction is stopped by adding 10 ml

Methylene chloride / methanol / conc. Ammonia 30/10/3 terminated and the suspension is filtered over a little silica gel with methylene chloride / methanol / conc. Ammonia 30/10/3 washed. It is then concentrated and the residue purified by flash chromatography (methylene chloride 30/5/1 then 30/10/3 then / methanol / conc. Ammonia 30/15/5) to give. This gives 580 mg of product 17 as an amorphous solid of molecular weight 631.20 (C 30 H 31 F 2 N 3 O 8 S); MS (ESI '): 629.79 (MH "4- (4-bromomethyl-2-Hydroxy-phenyl) -3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenvD-propyli- i - (4-fluoro-phenyl) azetidin-2-one 18

100 mg (0:18 mmol) of benzyl alcohol 14 is dissolved in 3 ml of DMF and cooled to 0 -4o C. Are added and stirred for 20 minutes at -40 0 C 180 mg triphenylphosphine (Aldrich). The reaction solution is diluted with 20 ml ethyl acetate and filtered over a little silica gel, concentrated, washed 3 times with aqueous NaCl solution and one obtains 100 mg of crude product. This crude product is dissolved in 20 ml THF and 10 ml of 2N aqueous HCl. After 18 hours at room temperature with 50 ml of ethyl acetate and washed after separating the aqueous phase 2 times with sodium bicarbonate solution, filtered through a little silica gel, concentrated and the residue purified by flash chromatography (n- heptane / ethyl acetate 2: 1 to 1: 2) cleaned. This gives 50 mg of benzyl bromide 18th

1- (4-Fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4- (2-hydroxy-4-piperazin-1-ylmethyl-phenyl) azetidin-2- on 19

40 mg (0.08 mmol) of bromide 18 is dissolved in 2 ml of acetonitrile. After addition of 50 mg of piperazine is stirred for 1 hour at room temperature. The suspension is evaporated and the residue with flash chromatography

(Methylene chloride / methanol / conc. Ammonik 30/5/1 then 30/10/3) to give. This gives 42 mg of amine 19th

4- (4- (1- (4-Fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-oxo-azetidin-2-yl} - 3-hydroxy-benzyl sulfamide ammonium salt (example B) -) piperazin-1

38 mg (0.075 mmol) of compound 19 are reacted analogously to the synthesis of Example A and Example B are obtained 30 mg as an amorphous solid with the molecular weight 587.11 (C 29 H 2 F 3I N 3 O 6 S); MS (ESI '): 586.11 (MH ").

4-methyl-piperazin-1-carbonic acid 4- {1- (4-fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-yl ) -3-Hydroxy-benzyl ester 20

200 mg (0:36 mmol) of benzyl alcohol 14 the synthesis of compound 15 and 16 are reacted analogously and one obtains 90 mg methylpiperazine 20 as an amorphous solid. 4- (4- (1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-yl) - 3-hvdroxy- benzyloxycarbonyl) -1.1-dimethyl-piperazin-1 -ium iodide (example C)

80 mg (0:14 mmol) of compound 20 are dissolved in 5 ml of toluene and heated to 80 0 C. To this solution is added dropwise 0.8 ml of methyl iodide and stirred for 1 hour at 80 0 C. The precipitated product is filtered, washed with toluene and is obtained 72 mg of a colorless solid of the ammonium salt Ex. C with molecular weight 580.26 (C 32 H 36 F 2 N 3 O 5); MS (ESI) 580.12 (M +).

4- (4- (1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-yl) - 3- hvdroxy- benzyloxycarbonylmethvD-i-methyl-pyridinium iodide (example D)

135 mg (0:24 mmol) of benzyl alcohol 14 is reacted analogously to the synthesis of the compound of Example C and obtained 53 mg of ammonium salt of Example D as a colorless solid of molecular weight 588.23 (C 33 H 32 F 2 N 3 O 5); MS (ESI) 588.36 (M +). scheme 2

DMSOZAc 2 O

2-benzyloxy-4-nitro-benzoic acid benzyl ester 21

75 g (410 mmol) of 4-nitro-salicylic acid (Aldrich) are dissolved in 1 l of DMF, and 190 ml of benzyl bromide. After addition of 200 g of K 2 CO 3, the suspension is stirred for 16 hours at room temperature vigorously. The reaction solution is stirred with 1 I ethyl acetate and 1 I of water for 15 minutes. The aqueous phase is separated off and the organic phase washed 2 times with saturated NaCl solution, filtered through silica gel and concentrated to crystallize until the product begins. The crystals are suction filtered (70g) and using n-heptane / ethyl acetate (4: 1) and dried. On concentrating the mother liquor another crystal fraction from falls (this can be repeated two times). Overall, one obtains 132 g of crystalline product 21st

2-benzyloxy-4-nitro-benzaldehyde 23

132 g (363 mmol) of the nitroaromatic compound 21 are reacted analogously to the synthesis of compound 7 and 8 and obtained aldehyde 23 as a colorless solid.

(2-benzyloxy-4-nitro-benzylidene) - (4-fluoro-phenyl) -amine 24

22.1 g (86 mmol) of aldehyde 23 and 12.0 g (108 mmol) of 4-9 Flouranilin the synthesis of imine 10 and are reacted analogously obtained imine 24 as a crystalline solid.

4- (2-benzyloxy-4-nitro-phenyl) -3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenyl) - propyli-1 - (4-fluoro-phenyl) azetidin-2-one 26

From 27.5 g (78.5 mmol) of imine 24 and 62.2 g (132 mmol) oxazolidinone 11 is obtained for analog preparation method as for compound 12 and 13, 24 g of beta-lactam 26 as an amorphous solid.

4- (4-amino-2-benzyloxy-phenyl) -3-R3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenvD-propylM - (4-fluoro-phenyl) azetidin-2 -one 27

24 g (36 mmol) of 26 is reacted analogously to the hydrogenation of compound 13, and obtained 13.2 g of aniline 27 as an amorphous solid.

Piperazin-1-carbonic acid (4- [3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenvD- propvl1-1- (4-fluoro-phenvl) -4-oxo- azetidin-2-vll-3-hvdroxv-phenyl) -amide 28

700 mg (1.3 mmol) of aniline are reacted analogously to the synthesis of amine 15 and 27 are obtained 347 mg of 28 as an amorphous solid.

Piperazine-1-carbonic acid (4- {1- (4-fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-hvdroxy- propyn-4-oxo-azetidin-2-yl) -3 -hvdroxy-phenyl) -amide 29

337 mg (0:52 mmol) of piperazine derivative 28 may be reacted analogously to the synthesis of compound 16, and obtained 217 mg of 29 as an amorphous solid of molecular weight 536.58 (C 29 H 30 F 2 N 4 O 4); MS (ESI +): 537.13 (M + H +).

4- (4- (1- (4-Fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-YLV 3- Hydroxy-phenylcarbamoyl) - piperazin-1-sulfamide ammonium salt 30 (example e)

370 mg (0.69 mmol) of compound 29 are reacted analogously to the synthesis of Example A and gives 343 mg of sulfamide 30 (Example E) as an amorphous solid of molecular weight 616.18 (C 29 H 30 F 2 N 4 O 7 S); MS (ESI +): 1233.28 (2M + H +).

4- (4-Amino-2-Hydroxy-phenyl) -1- (4-fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-hvdroxy- propyll- azetidin-2-one 31

2.5 g (3.8 mmol) of Compound 27 are silylentschützt analogous to the synthesis of compound 16, and obtained 1.23 g of aniline 31 as an amorphous solid.

(4- (1- (4-Fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-hydroxy-propyn-4-oxo-azetidin-2-yl) -3-hydroxy-phenyl) - sulfamide ammonium salt (example F)

44 mg (0.10 mmol) of aniline 31 are sulfated analogous to the synthesis of compound 30 120 mg of trimethylamine-sulfur dioxide complex, and obtained 21 mg of sulfamide Ex. F as an amorphous solid of molecular weight 504.12 (C 24 H 22 F 2 N 2 O 6 S); MS (ESI "): 503.25 (MH").

2,3,4,5,6-Pentahvdroxy-hexanoic acid (4- (1- (4-fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-4-oxo-propyπ azetidin-2-yl} -3-Hydroxy-phenyl) -amide (example G)

50 mg (0.12 mmol) of aniline and 100 mg of 31 (0:24 mmol) of penta-O-acetylgluconsäure are dissolved in 3 ml DMF. Are added to 150 mg of EDC and 75 mg of HOBt and stirred for 1 hour at room temperature. After addition of 20 ml ethyl acetate is washed 3 times with NaCl solution filtered through silica gel, concentrated and the residue purified by flash chromatography (n-heptane / ethyl acetate 1: 1: 1 to 0) cleaned. The obtained product (65 mg) is dissolved in 5 ml of methanol and 0.5 ml of 1 M NaOMe / MeOH. After 30 minutes at room temperature, neutralized with 0.5 M HCl / MeOH and concentrated, and the residue purified by flash chromatography (methylene chloride then 30/5/1 then / methanol / conc. Ammonia 30/10/3 30/15/5) columned. This gives 40 mg sugar derivative Ex G as an amorphous solid of molecular weight 602.59 (C 30 H 32 F 2 N 2 O 9). MS (ESI '): 601.40 (MH').

1-r (4- (1- (4-Fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-hydroxy-propyn-4-oxo-azetidin-2-yl) - 3-hvdroxy- phenylcarbamoyl) -methyll-4-aza-1-azonia-bicvclor2.2.2loctan iodide (example

H)

Ex. H 54 mg (0.13mmol) of aniline 31 and 150 mg of iodoacetic acid in analogy coupled with EDC / HOBt as in the synthesis of Ex. G described and obtained iodide 40 mg. This is dissolved in 5 ml of toluene and 1 ml of methylene chloride. After addition of 200 ml DABCO 1 hour at 80 0 C is stirred. The precipitate is filtered off and yields the Trialkylammoniumalkysalz Example H with the molecular weight 577.26 (C 32 H 35 F 2 N 4 O 4). MS (ESI) 577.20 (M +).

scheme 3

I 1 R = SO 3 NH 4 * 2,4-dibenzyloxy-benzaldehvd 33

50 g (362 mmol) of 2,4-dihydroxy-benzaldehyde 32 (Aldrich) in 800 ml DMF with 100 ml of benzyl bromide and 200 g of K 2 CO 3 the synthesis of 21 are analogous perbenzylated and one obtains 96 g of crystalline product 33rd

(2,4-dibenzyloxy-benzylidene) - (4-fluoro-phenyl) -amine 34

6.1 g (1.9 mmol) of aldehyde 33 is reacted with 3.0 g (2.7 mmol) 4-fluoroaniline 9 reacted analogously to the synthesis of imine 10 and obtained 6.0 g of crystalline imine 34th

3-r2-r (2 1 4-dibenzyloxy-phenyl) - (4-fluoro-phenylamino) -methyll-5- (tert-butyl-dimethyl-silanyloxy) -5- (4-fluoro-phenyl) -pentanoyll-4 phenyl-oxazolidin-2-one 35

5.0 g (10.6 mmol) oxazolidinone 11 and 8.0 g (19.4 mmol) of imine of the synthesis of compound 12 is reacted analogously to 34 and obtained 7.5 g Iminadditionsprodukt 35 as an amorphous solid.

3- [3- (tert-Butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyll-4- (2.4-dihvdroxy- phenyl) -1- (4-fluoro-phenyl) azetidin-2 -one 36

28.4 g (32.2 mmol) 35 in the synthesis of beta-lactam are cyclized analog 13 and obtained 13.1 g of lactam 36 as an amorphous solid.

4- (2-benzyloxy-4-Hydroxy-phenyl) -3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenyl) -propyπ-1- (4-fluoro-phenyl) azetidin-2-one 37

3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyn-4- (2,4-dihydroxy-phenyl) -1 - (4-fluoro-phenyl) -azetidin- 2-one 38

4- (4-benzyloxy-2-Hydroxy-phenyl) -3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenvD-propyli-i - (4-fluoro-phenyl) -azetidin -2-one 39

The partial hydrogenation of compound 36 provides a product mixture of 37:38:39 as 5.3: 1.7: 1st A full hydrogenation can obtain the diphenol 38 quantitatively.

13.1 g of lactone 36 (10% / Pd) bar hydrogenated for 3 hours at 5 hydrogen dissolved in 200 ml ethyl acetate and 2 g of Pd / C. The product mixture is purified by flash chromatography (n-heptane / ethyl acetate 3: 2: 1 to 1) separated. First eluted product 39, then 37 and most polar compound as the product 38. This gives 5.3 g of 37, 1.7 g of 38 and 1.0 g of 39, all as amorphous solids.

Piperazin-1-carbonic acid 3-benzyloxy-4- [3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4- fluoro-phenyl) -propyπ-1 - (4-fluoro-phenyl) -4 oxo-azetidin-2-vn-phenyl ester 40

1.0 g (1.6 mmol) of phenol 37 are umgestetzt with 1.0 g of di-SU-CO analogous to the synthesis of compound 15, and obtained 387 mg of piperazine derivative 40 and 405 mg of starting material 37 (this is formed from the intermediate stage by engagement of the piperazine at the phenolic side of the carbonyl group.

Piperazin-1 -kohlensaure {4-F3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenyl) - propyll-1- (4-fluoro-phenyl) -4-oxo-azetidin -2-yll-3-Hydroxy-phenyl) -amide 41

370 mg (0.50 mmol) of Compound 40 are analogous to the benzylentschützt Hydrierungsvorschrift of compound 14 and obtained 310 mg of piperazine derivative 41 as an amorphous solid. Piperazin-1-carbonic acid 4- {1- (4-fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-hvdroxy- propyll-4-oxo-azetidin-2-yl) -3- Hydroxy-phenyl ester 42

310 mg (0:48 mmol) of compound 41 can be deprotected with aqueous HCl (analog compound 16) and one obtains 124 mg of piperazine derivative 42 as an amorphous solid of molecular weight 537.57 (C 29 H 29 F 2 N 3 O 5); MS (ESI +): 538.18 (M + H +).

4- (4- (1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-yl) - 3- hvdroxy- phenoxycarbonyl) -piperazin-1-sulfamide ammonium salt 43 (example I)

70 mg (0.13mmol) 42 are reacted with the Sθ 3 -trimethylamine complex analogous to the synthesis of compound 17th This gives 77 mg Schwefelsäureamid- derivative 43 (Example I) as an amorphous solid of molecular weight 617.16 (C 29 H 29 F 2 N 3 O 8 S); MS (ESI +): 1235.05 (2M + H +). 4-methyl-piperazin-1-carbonic acid 4- (1- (4-fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-oxo-azetidin-2-yl ) -3-Hydroxy-phenyl ester, compound 70

The synthesis of compound 70 is carried out analogously to the preparation of compound 42nd Methylpiperazine is used in place of the piperazine. Molecular weight 551.60 (C 30 H 3 IF 2 N 3 O 5); MS (ESI +): 1103.08 (2M + H +).

4- (4- (1- (4-Fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-oxo-azetidin-2-yl) - 3- Hydroxy-phenoxycarbonyl ) -1.1-dimethyl-piperazin-1-ium iodide. example J

56 mg (0.10 mmol) of Compound 70 are analogous to the synthesis of compounds of Examples C quaternized with methyl iodide and obtained 62 mg of ammonium salt of Example J as a colorless solid of molecular weight 566.24 (C 3 i H 34 F 2 N 3 O 5). MS (ESI) 566.48 (M +). Sulfuric acid mono- (3- {3-benzyloxy-4-f3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenyl) -propyll-1- (4-fluoro-phenyl) - 4-oxo-azetidin-2-yll-phenoxy) -propyl) ester ammonium salt 44

1.21 g (1.9 mmol) of phenol 37 are dissolved in 30 ml DMF. After addition of 3.0 g (21 mmol) I .S-propanediol cyclic sulfate (Aldrich) and 4.5 g K 2 CO 3 was stirred 2 hours at room temperature. The reaction solution is made slightly acidic with 2N aqueous HCl and then extracted with ethyl acetate. The organic phase is washed 2 times with NaCl solution, then with methylene chloride / methanol / conc. basified ammonia (30/5/1) and concentrated. The residue is (then then methylene chloride / methanol / conc. Ammonia 100/7/1 30/10/3 30/5/1) and purified by flash chromatography to obtain 1.08g ammonium salt 44th

Sulfuric acid mono- (3- (4- [3-R3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) - propyll-1- (4-fluoro-phenyl) -4-oxo azetidin-2-vn-3-Hydroxy-phenoxy) -propyl) ester ammonium salt 45

1:07 g (1:39 mmol) of 44 in 20 ml of methanol with 200 mg Pd / C (10% Pd) for 2 hours at 5 bar hydrogen and hydrogenated to obtain 979 mg of crude product 45th

Sulfuric acid mono- [3- (4- (1- (4-fluoro-phenyl) -3-F3- (4-fluoro-phenyl) -3-hydroxy-propyπ-4-oxo-azetidin-2-yl) - 3-hydroxy-phenoxy) -propynester ammonium salt, example K

1.5 g of crude product 45 to be 18 hours in a mixture of 40 ml THF and 10 ml of 2 N aqueous HCl, allowed to stand. The solution is diluted with 50 ml

Methylene chloride / methanol / conc. Ammonia (30/10/3) diluted (until the solution is basic) and concentrated. The residue is suspended in 30/5/1 and filtered through a little silica gel, evaporated down and the residue obtained by flash chromatography (methylene chloride / methanol / conc 30/10/3 with. Ammonia 30/5/1 then 30/10/3 then 30/15/5) separately. This gives 1.03 g of ammonium salt of Example K with molecular weight 563.14 (C 27 H 27 F 2 NO 8 S). MS (ESI +): 1127.14 (2M + H +).

(4-iodo-butoxymethyl) -benzene 46

10 g (55.5 mmol) of 4-benzyloxy-1-butanol (Aldrich) are dissolved in 200 ml of toluene. Then, in succession, 6 g (88 mmol) of imidazole, 17 g (64 mmol) of triphenylphosphine and then 17 g (67 mmol) of iodine was added under vigorous stirring. After stirring for 2 hours, treated with 200 ml of saturated sodium bicarbonate solution and as much iodine is added until the organic phase remains dark. The excess iodine is reduced with 10% sodium thiosulfate solution, the organic phase separated washed once with NaCl solution, filtered through silica gel and then concentrated. The precipitated triphenylphosphine oxide is separated and concentrated the mother liquor. This gives 15.8 g of crude product 46th

4-r2-Benzyloxy-4- (4-benzyloxy-butoxy) -phenvn-3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-f luoro-phenyl) -propyn-1 - (4 -f luoro-phenyl) azetidin-2-one 47

0.5 g (0.79 mmol) of phenol 37 are with 700 mg (2.4 mmol) of iodide 46 and 650 mg K 2 CO 3 in 15 ml DMF alkylated analogously to the synthesis of compound 44, and obtained 300 mg of 47 as an amorphous solid.

3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyll-1- (4-fluoro-phenyl) -4-r2-Hydroxy-4- (4-Hydroxy-butoxy ) -phenvn-azetidin-2-one 48

300 mg (0:38 mmol) of 47 methanol with 60 mg Pd / C (10% Pd) is hydrogenated for 18 hours at 5 bar hydrogen in 3 ml. After flash chromatography to obtain 155 mg of alcohol 48th

Sulfuric acid mono- (4- (4- [3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) - propyll-1- (4-fluoro-phenyl) -4-oxo azetidin-2-yll-3-hydroxy-phenoxy) butyl) -ester ammonium salt 49

150 mg (0:25 mmol) of 48 are dissolved in 2 ml of pyridine. After addition of 170 mg Trimethylaminschwefeltrioxid complex 1 hour at room temperature is stirred. Then, it is diluted with 10 ml of methanol and 10 ml of toluene and concentrated. The residue was columned by flash chromatography (methylene chloride / methanol / conc. Ammonia 30/5/1 then 30/10/3) and obtained 150 mg sulphate 49th

Sulfuric acid mono-F4- (4- (1- (4-fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-hvdroxy- propyll-4-oxo-azetidin-2-yl} - 3-Hydroxy-phenoxy) -butyl1 ester ammonium salt, example

150 mg (0:22 mmol) of 49 the synthesis of compound K example TBDMS be deprotected analog and one obtains 69 mg sulphate Example L with molecular weight 577.19 (C 28 H 29 F 2 NO 8 S); MS (ESI +): 578.26 (M + H +).

4-r2-Benzyloxy-4- (4-bromo-but-2-enyloxy) -phenyll-3-R3- (tert-butyl-dimethyl-silanyloxy) - 3- (4-fluoro-phenyl) -propyll-1- (4-fluoro-phenyl) azetidin-2-one 50

200 mg (0.32 mmol) of phenol 37 in 5 ml of DMF with 600 mg (2.8 mmol) is alkylated 1,4-dibromo-2-butene and 600 mg of K 2 CO 3 and obtained 220 mg bromide 50th

4-r2-Benzyloxy-4- (4-imidazol-1-yl-but-2-enyloxy) -phenyll-3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyn-1- (4-fluoro-phenyl) azetidin-2-one 51

210 mg (0:28 mmol) of 50 are dissolved in 5 ml of toluene and after adding 400 mg of imidazole for 1 h at 60 0 C stirred. The reaction solution is concentrated and the residue Flaschchromatographie (methylene chloride then 100/7/1 / methanol / conc. Ammonia 30/5/1) cleaned. This gives 155 mg of product 51st

1- (4-Fluoro-phenyl) -3-R3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-f2-hydroxy-4- (4-imidazol-1-yl-butoxy) -phenyll- azetidin-2-one, compound 71

155 mg (0:21 mmol) of 51 are analogous to the synthesis of Example K and benzyl silylentschützt and one obtains 75 mg imidazole derivative 71 with the molecular weight 547.61 (C H 3 3I IF 2 N 3 O 4). MS (ESI +): 548.23 (M + H +).

3- [4- (4- {1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyn-4-oxo-azetidin-2-yl) -3 -hvdroxy-phenoxy) -butvH-1-methyl-3H-imidazol-1-ium iodide, example M

55 mg (0.10 mmol) 71 are dissolved in 2 ml of toluene. After addition of 2 ml of methyl iodide is load-refluxing for 3 hours at 80 0 C oil bath temperature. After suction filtration of the precipitated product M is obtained 46 mg Example as a colorless solid of molecular weight 562.25 (C 32 H 34 F 2 N 3 O 4). MS (ESI) 562.11 (M +). 4-r4-benzyloxy-2- (2-trimethylsilanyl-ethoxymethoxy) -phenvn-3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyn-1- (4-fluoro phenyl) azetidin-2-one 53

1.0 g (1:59 mmol) of phenol 39 with 0.8 ml are SEMCI (Aldrich) and 1.2 g K 2 CO 3 in 5 ml of DMF and reacted to obtain 1.3 g SEM-protected phenol 53rd

3-R3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyll-1- (4-fluoro-phenyl) -4- [4-Hydroxy-2- (2-trimethylsilanyl- ethoxymethoxy) -phenvn-azetidin-2-one 54

1.1 g (1.4 mmol) of 53 are treated with Pd / C in analogy to the synthesis of compound 14 and hydrogenated to obtain 0.9 g of phenol 54th

4-F4- (4-bromomethyl-benzyloxy) -2- (2-trimethylsilanyl-ethoxymethoxy) -phenyll-3- [3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro-phenyl) -propyll -1- (4-fluoro-phenyl) -azetidin- 2-one 55

0.9 g (1.3 mmol) of phenol 54 are with 2.5 g (9.5 mmol) of p-xylene dibromide (Aldrich) and 2.5 g K 2 CO 3 in 30 ml DMF and reacted to obtain 0.6 g of bromide 55th

4-F4- (4-bromomethyl-benzyloxy) -2-Hydroxy-phenyll-1- (4-fluoro-phenyl) -3-F3- (4-fluoro- phenyl) -3-Hydroxy-propyll-azetidin-2- on 56

0.6 g (0.7 mmol) 55 are dissolved in 30 ml THF. After addition of 6 ml 2N aqueous HCl seven hours is heated to 60 0 C. The reaction solution is diluted with 100 ml of ethyl acetate, the aqueous phase separated, the organic phase is washed twice with NaHCO 3, filtered through a little Kiselgel and concentrated. The residue is purified by flash chromatography (n.Heptan / ethyl acetate 1: 1) and separated to obtain 340 mg deprotected bromide 56th

1-r4- (4- {1- (4-Fluoro-phenyl) -3- [3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4-oxo-azetidin-2-yl) -3- Hydroxy-phenoxymethyl) -benzvn-4-aza-1-azonia-bicvclor2.2.2loctan bromide, example N

122 mg (0:20 mmol) of 56 are dissolved in 5 ml of toluene, and 150 mg DABCO 2 hours at 80 0 C stirred. The precipitated product is filtered off, washed with toluene and is obtained 138 mg Trialkylammoniumalkylsalz Example N with the molecular weight 640.30 (C 38 H 40 F 2 N 3 O 4). MS (ESI) 640.38 (M +).

scheme 4

(4 - [(2-benzyloxy-4-methoxy-benzylidene) -amino1-benzyl) -carbamic acid benzyl ester

59

8 g (33 mmol) of aldehyde 57 and 10 g (crude product) aniline 58 is reacted analogously to the synthesis of imine 10 and obtained 6.5 g of crystalline product 59th

(4- [1- (2-benzyloxy-4-methoxy-phenyl) -5- (tert-butyl-dimethyl-silanyloxy) -5- (4-fluoro- phenyl) -2- (2-oxo-4-phenyl -oxazolidines-3-carbonyl) -pentylaminol-benzyl} - carbamic acid benzyl ester 60

2.5 g (7.0 mmol) oxazolidinone 11 and 3.0 g (6.2 mmol) of imine 59 is reacted analogously to the synthesis of compound 12, and obtained 1.78 g of product 60 and 1.5 g of recovered starting material. 11

(4- {2- (2-benzyloxy-4-methoxy-phenyl) -3-F3- (tert-butyl-dimethyl-silanyloxy) -3- (4-fluoro- phenyl) -propyn-4-oxo-azetidin 1-yl) benzyl) -carbamic acid benzyl ester 61

1.78 g (1.9 mmol) of 60 in the synthesis of beta-lactam are cyclized analog 13 and obtained 880 mg of product 61st

1- (4-aminomethyl-phenyl) -3-F3- (4-fluoro-phenyl) -3-Hydroxy-propyll-4- (2-Hydroxy-4-methoxy-phenyl) azetidin-2-one 62

860 mg (1.1 mmol) of 61 are analogous to the synthesis of Ex. O benzyl and silylentschützt and obtained 300 mg beta-lactam 62 as an amorphous solid.

11- (2, 3,4,5, 6-Pentahvdroxy-hexanoylamino) undecanoic acid-4- [3-R3 (4-fluoro-phenyl) -3-Hydroxy-propyll-2- (2-Hydroxy-4- methoxy-phenyl) -4-oxo-azetidin-1-vn-benzylamide, example O

Ex. O 60 mg (0:11 mmol) of benzylamine 62 are anoalg Ex. G with 200 mg of acid 63, 150 mg EDC and 75 mg HOBt in 5 ml DMF umgestetzt (16 hours at room temperature) and one obtains 50 mg acylated Example O. This intermediate is deprotected with MeOH / NaOMe and isolating 29 mg sugar derivative Ex O as an amorphous solid of molecular weight 811.95 (C 43 H 58 FN 3 O 11). MS (ESI +): 812.42 (M + H +).

(4-f3-F3- (4-Fluoro-phenyl) -3-Hydroxy-propyn-2- (2-Hydroxy-4-methoxy-phenyl) -4-oxo-azetidin-1-vπ-benzyl) carbamic acid, 2,5-dioxo-pyrrolidin-1-yl ester 64

100 mg (0:22 mmol) of 62 are dissolved in 5 ml of acetonitrile and stirred with 100 mg of di-Su-CO 1 hour at room temperature. After concentrating the reaction solution, the residue is purified by flash chromatography (n-heptane / ethyl acetate 1: 2 then 0: 1) and obtained 60 mg 64th

1-r2- (4- {4- [3-R3 (4-Fluoro-phenyl) -3-Hydroxy-propyn-2- (2-Hydroxy-4-methoxy-phenyl) -4-OXO azetidin-1 -yll-benzylcarbamoyl) -piperazin-1-yl) -2-oxo--ethyl-4-aza-1 -azonia- bicyclo [2.2.21octane chloride example P

60 mg (0.10 mmol) 64 are dissolved in 3 ml acetonitrile. After adding 40 mg of piperazine derivative 65 and 0.3 ml of 1 N aqueous sodium hydroxide solution is stirred for 4 hours at room temperature. The reaction solution is eingengt to 1 ml, diluted with 1 ml DMF and purified by preparative HPLC. This gives 23 mg of ammonium salt of Example P with the molecular weight 715.36 (C 39 H 48 FN 6 O 6). MS (ESI) 715.34 (M +).

The compounds of formula I of the invention were tested using the method described below for their effect:

Influence on Cholesterol Absorption + 3 H Taurocholsäureausscheidung based on the fecal excretion of the mouse, rat or hamster

NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n = 4-6) are kept in metabolic cages with a standard diet (Altromin, Lage (Lippe)). In the afternoon prior to the administration of the radioactive tracers (14 C-cholesterol), the animals are fasted and adapted to grates.

In addition, the animals will be 24 hours prior to the peroral administration of the test meal (14 C-cholesterol in Intralipid 20, Pharmacia-Upjohn) with 3 H-TCA (Taurocholic acid) labeled (eg, 1 uCi / mouse to 5 uCi / rat) sc

Cholesterol absorption test: 0.25 ml / mouse Intralipid ® 20 (Pharmacia-Upjohn) ((spiked with 0.25 uCi 14 C-cholesterol in 0.1 mg of cholesterol) are administered perorally by gavage Test substances are separated in 0.5%. / (methylcellulose (Sigma) / 5% Solutol (BASF, Ludwigshafen) or a suitable vehicle applied. the administration volume of the test substance is 0.5 ml / mouse. the test substance is administered immediately prior to the test meal (Intralipid (14 C-cholesterol label) cholesterol absorption test) administered orally.

Feces are collected for 24 h. Fecal elimination of 14 C-cholesterol and 3H-taurocholic acid (TCA) is determined after 24 hours.

The livers are removed and homogenized, and aliquots incinerated in an oximate (Model 307, P Paacckkaarrdd)) for determining the vveerbrannt taken up / absorbed amount of 14 C-cholesterol.

Evaluation: faecal samples:

It is determined the total weight, filled with water to a defined volume and then homogenized, burned aliquot dried and incinerated in an oximate (Model 307 from Packard for the incineration of radioactively labeled samples): the amount of radioactive 3 H-H 2 O and 14 C CO 2 is extrapolated to the excreted amount of 3 H-taurocholic acid and 14 C-cholesterol (dual isotope technique). The ED 2O o-values are interpolated as dose from a dose-effect curve as those doses at which double the excretion of TCA or cholesterol relative to a control group treated at the same time.

Liver samples:

The absorbed amount of 14 C-cholesterol in the liver is analyzed as a function of the applied dose of the test substance relative to a control group (vehicle treated). The ED50 values are interpolated from a dose-effect curve as the dose which bisects the uptake of 14 C-cholesterol in the liver (50%), based on a control group. The following ED 50 values (liver values; mouse) demonstrate the activity of the compounds of the formula I

Example no. EDSN (liver) [mq / Mausl

0 <0.01 M <0.1 A 0:01 P 0.3 B <0.1

1 00:01 00:01 H F 0.3 E <0.01 C 0.1

K <0.01

N 12:01

From the table it can be read that the compounds of the formula I very well inhibit the absorption of cholesterol from the gastrointestinal tract.

Hamster Model:

Syrian hamsters (in groups of n = 5-9) received a 0.1% cholesterol-enriched standard diet (ssniff, Soest Germany).

The test substances are (in 0.5% / (methylcellulose Sigma) / 5% Solutol (recognized BASF, Ludwigshafen) or other suitable vehicle and administered a minimum of 3 doses of 12 aufeinader following days once a day by gavage. On day 12, the bled animals under deep anesthesia from the aorta. the serum total cholesterol, LDL analyzed cholesterol, HDL cholesterol and triglycerides with standard kit from Roche according to the guidelines of the German Society for Clinical Chemistry.

The ED 50 values for LDL cholesterol lowering cholesterol compared to placebo-treated control animals were calculated using a standard logistic model for dose response curve.

Data from hamster Try:

The following ED 50 values (serum LDL cholesterol; hamster, [mg / kg]) demonstrate the activity of the compounds of the formula I:

Example no. ED50

A 0.2

I <0.1

I 0.1

Liver exposure:

The liver exposure of the compounds of the invention over the corresponding compounds without a hydroxy function at 2 'position was investigated in vivo on male Wistar rats. At the anesthetized with ketamine / midazolam (ketamine 80 mg / kg ip + midazolam 5 mg / kg ip) anesthetized rat is administered intraduodenally, the preparation after laparotomy in the linea alba. Here, it is attempted to prevent a direct reflux of the preparation in the stomach. the animals remain during the entire experiment under anesthesia. at the end of the experiment, after 2 h, is used for the substance determining the liver dissected. the determination of the substance levels in liver homogenates by means of LC-MS / MS. For this purpose, the proteins by the addition of Acetoniril in the presence of an internal standard are first precipitated. a portion of the supernatant is mixed with a suitable buffer, and an aliquot of the mixture is injected. the evaluation of the measurement via the peak areas of analyte and i nternem standard. Results:

Cm ax values in the liver (L) after oral administration of 10 mg / kg body weight

"H-compounds" "2" -OH compounds "

example K

L = 24.3 ug / mL L = 0:30 ug / mL

example N

L = 0:20 ug / mL L = 0:08 ug / mL

From these data it can be read that the compounds of the invention have significantly lower liver mirror and so reduce the burden of the liver.

Claims

claims:
1. Compounds of the formula I 1
wherein mean
R1, R2, R3, R4, R5, R6 are independently (Ci-C 30) alkylene- (LAG) n, where n = 1 - 5 can be and where one or more carbon atoms of the
Alkylene group represented by -S (O) n -, with n = 0 - 2, -O-, - (C = O) -, - (C = S) -, -CH = CH-, -C≡C-, - N ((Ci-C 6) -alkyl) -, -N (phenyl) -, -N ((C r C6) -alkyl-phenyl) -, -N (CO- (CH2) i-io-COOH ) -, -N (CO- (C r C 8) alkyl) -, -N (CO- (C 3 -C 8) cycloalkyl), N (CO- (CH 2) o-io-aryl), -N (CO- (CH 2) o-io-heteroaryl), -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C 3 -C 0) cycloalkyl or heterocycloalkyl may be substituted;
H, F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (dC 6) alkyl, CONH 2, CONH (C 1 -C 6) alkyl, CON [(Ci-C 6 ) alkyl] 2, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, O- (Ci-C 6) -alkyl, where in the alkyl radicals , several, or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C r C 6) -alkyl, SO 2 N [(C r C6) alkyl] 2, S- (Ci-C 6) -alkyl, S- (CH 2) n -phenyl, SO- (C 1 -C 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - (C 1 -C 6) -alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times, by F, Cl, Br, OH, CF 3, NO 2, CN OCF 3, O- (Ci-C 6) -alkyl, (C r C6) alkyl, NH 2 may be substituted; NH 2, NH- (Ci-C 6) -alkyl, N ((C r C6) alkyl) 2, NH (Ci-C7) -acyl, phenyl, O- (CH 2) n -phenyl, where n = O - can be 6, wherein the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-
(Ci-C 6) -alkyl, (C r C6) alkyl, NH 2, NH (C r C6) alkyl, N ((CrC 6) alkyl) 2, SO 2 - CH 3, COOH, COO- (Ci-C 6) -alkyl, CONH 2;
R7 F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COOCd-CeJAlkyl, CONH 2, CONH ^ -CeOAlkyl, CONKd-CeJAlkylk, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 -
C 6) alkynyl, O- (Ci-C 6) -alkyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (CrC 6) alkyl, SO 2 Nt (C 1 - C 6) alkyl] 2, S- (Ci-C 6) -alkyl, S- (CH 2) n -phenyl, SO- (dC 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - (dC 6) alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times (with F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, O- C r 6) -alkyl, NH 2 may be substituted C6) alkyl, (Ci-C; NH 2, NH- (C 1 -C 6) -alkyl, N ((Ci-C 6) -alkyl) 2, NH (Ci-C7) acyl, aryl, O- (CH 2) n - aryl, wherein n = O - can be 6, wherein the aryl ring can be a to 3-fold substituted by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, 0- (Ci-C 6) -
Alkyl, (Ci-C 6) -alkyl, NH 2, NH (C 1 -C 6) -alkyl, N ((C 1 -C 6) -alkyl) 2, SO 2 -CH 3, COOH, COO- ( Ci-C 6) -alkyl, CONH 2;
LAG C 4 -Cio-cycloaliphatic having 2 to 9 hydroxyl-substituted radical or Cz-do-aliphatic having 2 to 10 hydroxyl substituted radical, wherein one or more hydroxy groups may be replaced by a -NHR8 group;
Amino acid residue, oligopeptide residue comprising 2 to 9 amino acids; acyclic, mono- or bicyclic trialkylammonium radical, acyclic, mono- or bicyclic Thalkylammoniumalkyl radical, where up to three carbon atoms may be replaced by N, O or S (O), with n = 0-2; N-alkylated heteroaromatics such. B. imidazolium or pyridinium;
-O- (SO 2) -OH; - (CH 2) O-IO -SO 3 H; - (CH 2) o-io-P (0) (OH) 2, - (CH 2) o-io-0- P (O) (OH) 2, - (CHz) o.io-C (= NH ) (NH 2); - (CH 2) 0- io-C (= NH) (NHOH); -NR8- C (= NR9) (NR10R11); wherein n = 1 - 5 and R8, R9, R10 and R11 independently of one another H, (Ci-C 6) alkyl, phenyl, (CrC 6) alkyl-phenyl,
(C 3 -C 8) cycloalkyl), -C (O) - (Ci-C 6) alkyl, -C (O) - (C 3 -C 8) cycloalkyl may be;
where always at least one of the radicals R1 to R6 has the meaning (Ci-C 3 o) -alkylene- (LAG) n, where n = 1 - 5 can be and where one or more C
Atoms of alkylene group represented by -S (O) n -, with n = O - 2, -O-, - (C = O) -, - (C = S) -, -CH = CH-, - C≡C- , -N ((Ci-C 6) -alkyl) -, -N (phenyl) -, -N ((C 1 -C 6) -alkyl-phenyl) -, -N (CO- (CH 2) 1- 10 - COOH) -, -N (CO- (Ci-C 8) -alkyl) -, -N (CO- (C 3 -C 8) cycloalkyl), N (CO- (CH 2) o-io- aryl), - N (CO- (CH2) io-0- heteroaryl), -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C 3 -C 0) - cycloalkyl or heterocycloalkyl can be replaced; must have,
as well as their pharmaceutically acceptable salts.
2. Compounds of formula I according to claim 1, characterized in that the meanings are
R1, R2, R3, R4, R5, R6 are independently (Ci-C20) -alkylene- (LAG), where one or more carbon atoms of the alkylene group by -O-, - (C = O) -, - N ((C 1 -C 6) alkyl) -, -N (CO- (CH 2) L IO -COOH) - or -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times with R7 may be substituted (C 3 -C 0) -cycloalkyl or heterocycloalkyl radicals substituted;
H, F, Cl, Br, I, CF 3, NO 2, N 3, CN, COOH, COO (Ci-C 6) alkyl, CONH 2,
CONH (Ci-C 6) alkyl, CON [(dC 6) alkyl] 2, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, O- (CrC 6) -alkyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (dC 6) -alkyl, SO 2 N f (C 1 - C 6) alkyl] 2, S- (dC 6) -alkyl, S- (CH 2) n -phenyl, SO- (Ci-C 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - (dC 6) alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times, by F, Cl, Br, OH, CF 3, NO 2
CN, OCF 3, O- (C 1 -C 6) alkyl, (C 1 -C 6) -alkyl, NH 2 may be substituted; NH 2, NH- (C 1 -C 6) -alkyl, N ((dC 6) alkyl) 2, NH (C r -C 7) -acyl, phenyl, O- (CH 2) n -phenyl, where n = O - can be 6, wherein the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (Ci-C 6) alkyl , (C r C6) alkyl, NH 2, NH (C 1 -Ce) -alkyl 1 N ((Ci-C 6) -alkyl) 2, SO 2 -
CH 3, COOH, COO- (CrC 6) alkyl, CONH 2;
R7 F, Cl, Br, I 1 CF 3, NO 2, N 3, CN, COOH, COO (Ci-C 6) alkyl, CONH 2,
CONH (Ci-C 6) AIKyI 1 CON [(Ci-C 6) -alkyl] 2, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, O- (CrC 6) -alkyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (Ci-Ce) -alkyl Nf 1 SO 2 (C 1 - C 6 J-AIKyI] 2 , S- (Ci-Ce) -alkyl 1 S- (CH 2) n -phenyl, SO- (dC 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - (dC 6) alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times, by F, Cl, Br, OH, CF 3, NO 2
CN, OCF 3, O- (Ci-C 6) -alkyl, (CrC 6) alkyl, NH 2 may be substituted; NH 2, NH- (Ci-Ce) -alkyl 1 N ((Ci-C 6) -alkyl) 2, NH (dC 7) acyl, aryl, O- (CH 2) n - aryl where n = O - 6 may be, wherein the aryl ring can be a to 3-fold substituted by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, 0- (C 1 -C 6) - AIKyI 1 (C 1 -Ce) -alkyl, NH 2, NH (CRCE) -alkyl 1 N ((dC 6) -alkyl) 2, SO 2 -CH 3,
COOH, COO- (CRCE) -alkyl 1 CONH 2;
LAG C 4 -Cio-cycloaliphatic having 2 to 9 hydroxy substituted
Radical or C 2 -do-substituted aliphatic radical with 2 to 10 hydroxy groups, wherein one or more hydroxy groups may be replaced by a -NHR8 group; Amino acid residue, oligopeptide residue comprising 2 to 9 amino acids; acyclic, mono- or bicyclic trialkylammonium radical, acyclic, mono or bicyclic trialkylammoniumalkyl radical, where up to three carbon atoms may be replaced by N, O or S (O), with n = 0-2; N-alkylated heteroaromatics such. B. imidazolium or pyridinium;
-O- (SO 2) -OH; - (CH 2) OI 0 -SO 3 H; - (CH 2) o-io-P (0) (OH) 2, - (CH 2) 0- io-O- P (O) (OH) 2, - (CH 2) o-io-C (= NH) (NH 2); - (CH 2) 0- io-C (= NH) (NHOH); -NR8- C (= NR9) (NR10R11); wherein n = 1 - 5 and R8, R9, R10 and R11 independently of one another H, (Ci-C 6) alkyl, phenyl, (Ci-CβJ-alkyl-phenyl, (C 3 -C 8) cycloalkyl), may be (C 3 -C 8) cycloalkyl, -C (O) - - (C r C6) alkyl, -C (O);
where always at least one of the radicals R1 to R6 has the meaning (Ci-C20) -alkylene- (LAG), where one or more carbon atoms of the alkylene group by -O-, - (C = O) -, -N (( Ci-C 6) -alkyl) -, -N (CO- (CH 2) I-Io-COOH) - or -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times by R7 substituted (C 3 -C 0) cycloalkyl or heterocycloalkyl radicals may be replaced; must have,
and their physiologically acceptable salts.
3. Compounds of formula I according to claim 1 or 2, characterized in that the meanings are
R1, R3 is H or (Ci-Ci 2) independently of one another -alkylene- (LAG), where one or more carbon atoms of the alkylene group by -O-, - (C = O) -, -N (CH 3) - or -NH- or substituted by up to three times by R7-substituted aryl or heteroaryl radicals or by up to four times substituted with R7 (C3-C10) - cycloalkyl or heterocycloalkyl radicals may be replaced, wherein one of the radicals R1 and R3 always is H and the other the
Is (Ci-Ci 2) -alkylene- (LAG) has. R2, R4, R5, R6 H;
R7 F, Cl, Br, I 1 CF 3, NO 2, N 3, CN, COOH, COO (Ci-C 6) alkyl, CONH 2,
CONH (C r C6) alkyl, CON [(dC 6) alkyl] 2, (Ci-C 6) -alkyl, (C 2 -C 6) alkenyl, (C 2 - C 6) alkynyl, O- (Ci-C 6) -alkyl, where in the alkyl radicals, more than one or all hydrogen (s) may be replaced by fluorine; C (= NH) (NH 2), PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (C 1 -C 6) -alkyl, SO 2 N [(C r C6) alkyl ] 2, S- (C 1 -C 6) -alkyl, S- (CH 2) n -phenyl, SO- (Ci-C 6) -alkyl, SO- (CH 2) n -phenyl, SO 2 - ( iC C 6) -alkyl, SO 2 - (CH 2) n -phenyl, where n = O - 6 and the phenyl radical can be up to two times by F, Cl, Br, OH, CF 3, NO 2,
CN, OCF 3, O- (Ci-C 6) -alkyl, (Ci-C 6) -alkyl, NH 2 may be substituted; NH 2, NH- (Ci-C 6) -alkyl, N ((Ci-C 6) -alkyl) 2, NH (C 1 -Cy) -acyl, aryl, O- (CH 2) n - aryl, where n = O - 0- (C 1 -C 6) may be 6, wherein the aryl ring can be a to 3-fold substituted by F, Cl, Br, I 1 OH, CF 3, NO 2, CN, OCF 3, - alkyl, (C r C6) alkyl, NH 2, NH (C 1 -C 6) -alkyl, N ((C 1 -C 6) -alkyl) 2, SO 2 -CH 3,
COOH, COO- (Ci-C 6) -alkyl, CONH 2;
LAG C 4 -C 10 -cycloaliphatischer substituted with 2 to 9 hydroxy
Radical or C 2 -Cio-substituted aliphatic radical with 2 to 10 hydroxy groups, wherein one or more hydroxy groups may be replaced by a -NHR8 group;
Amino acid residue, oligopeptide residue comprising 2 to 9 amino acids; acyclic, mono- or bicyclic trialkylammonium radical, acyclic, mono or bicyclic trialkylammoniumalkyl radical, where up to three carbon atoms may be replaced by N, O or S (O), with n = 0-2; N-alkylated heteroaromatics such. B. imidazolium or
pyridinium;
-O- (SO 2) -OH; - (CH 2) O-10 -SO 3 H; - (CH 2) 0-10 -P (O) (OH) 2, - (CH 2) 0-10 -O-
P (O) (OH) 2, - (CH 2) 0-10 -C (= NH) (NH 2); - (CH 2) o-io-C (= NH) (NHOH); -NR8- C (= NR9) (NR10R11); wherein n = 1 - 5 and R8, R9, RIO and R11 independently of one another H, (Ci-C 6) alkyl, phenyl, (dC ^ alkyl-phenyl,
(C 3 -C 8) cycloalkyl), -C (O) - (Ci-C 6) alkyl, -C (O) - (C 3 -C 8) cycloalkyl may be;
and their physiologically acceptable salts.
4. Compounds of formula I according to one or more of claims 1 to 3, characterized in that the meanings are
LAG - (CH 2) o-io-0- (Sθ 2) -OH, - (CH 2) o-io-S0 3 H or a mono- or bi- cyclic trialkylammoniumalkyl radical in which up to three carbon atoms are replaced by N, O or S (O) n, may be replaced with n = 0-2;
and their physiologically acceptable salts.
5. Compounds according to one or more of claims 1 to 4 for use as a medicament.
6. A medicament comprising one or more of the compounds according to one or more of claims 1 to. 4
7. A medicament comprising one or more of the compounds according to one or more of claims 1 to 4 and at least one further active compound.
8. A pharmaceutical composition according to claim 7, characterized in that it comprises as further active ingredient one or more antidiabetics, hypoglycemic active ingredients, HMGCoA
Reductase inhibitors, Cholesterinresorptionsinhibitoren, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid, MTP inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, beta cells acting agents, glycogen phosphorylase inhibitors, glucagon receptor antagonists , activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1, 6-bisphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphate ase-1B, modulators of the sodium-dependent glucose transporter 1 or 2, modulators of GPR40, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists,
Inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, .beta.3 agonists , CB1 receptor antagonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, decoupling protein 2- or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR-.beta.-agonists or amphetamines contains.
9. Use of the compounds according to one or more of claims 1 to 4 for preparing a medicament for lowering blood sugar.
10. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of type Il diabetes.
11. Use of the compounds according to one or more of claims 1 to 4 for preparing a medicament for treating lipid and carbohydrate metabolism disorders.
12. Use of the compounds according to one or more of claims 1 to 4 for preparing a medicament for treating arteriosclerotic symptoms.
13. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of insulin resistance.
14. A method for producing a medicament comprising one or more of the compounds according to one or more of claims 1 to 4, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.
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